Zoledronic Acid, sold as Zometa/Aclasta/Reclast, is a nitrogen containing bisphosphonate that is used for treatment of hypercalcemia of malignancy, for the treatment of bone metastasis associated with malignancies such as prostate and breast cancer, for the prevention of and treatment of osteoporosis and for the treatment of Paget's disease.
The patent for Zoledronic Acid is held by Novartis and it expires in 2012.
Zoledronic Acid is administered by an intravenous infusion of 4 mg every 3-4 weeks (Zometa) for multiple myeloma and bone metastasis of other malignancies or 5 mg once a year (Aclasta/Reclast) for non-oncology indications. It is also used for the treatment of hypercalcemia of malignancy.
Administration of Zometa is complicated by what is described as “post-dosing syndrome” (PDS) which affects as much as 44% of patients as described in the Zometa Prescribing Information (http://www.pharma.us.novartis.com/product/pi/pdf/Zometa.pdf). The syndrome is characterized by fever, nausea, bone pain, arthralgia, myalgia, chills, etc.
The etiology of this syndrome has not been identified, but is associated with an increase in levels of tumor necrosis factor (TNF), interleukin 6 (IL-6), and gamma interferon (γIFN) (Dicuonzo G et al 2003, Schweitzer D H et al 1995, Thiebaud D et al 1997). These cytokines are usually produced by T cells.
Zoledronic acid can cause stimulation of a subset of T cells known as gamma delta (γδ) T cells (Mariani S et al 2005). These cells, specifically Vγ9/Vδ2 T cells, can constitute up to 10% of circulating CD3 T cells when stimulated.
Upon stimulation by Zoledronic Acid, these γδ T cells produce interleukin 2 (IL-2) and TNF. IL-2 in turn can stimulate the production of other cytokines such as IL-6 and γIFN. Thus, treatment with Zoledronic Acid can stimulate a subset of T cells that may lead to post-dosing syndrome by production and release of pro-inflammatory cytokines.
Probably the most serious side effect with not only zoledronic acid but all bisphosphonates (BPs) is osteonecrosis of the jaw (ONJ). Patients receiving BPs who have pre-existing dental abnormalities can develop potentially fatal ONJ. Predisposing factors for the development of osteonecrosis of the jaw appear to be dental disease, dental surgery (e.g., tooth extraction), oral trauma, periodontitis, and poor dental hygiene. The risk factors for developing ONJ include trauma, female gender, advanced age, edentulous regions, radiotherapy, chemotherapy, prolonged high dose steroid therapy, blood dyscrasias/metastatic disease, anemia, coagulopathy, surgical dental procedures, alcohol or tobacco use, prior infection, and bisphosphonate therapy (Masoodi, N A 2009).
The incidence of ONJ is less than one in 10,000 in patients with osteoporosis (Masoodi N A, 2009), but is much higher in patients with myeloma and breast cancer (Woo S B, 2006). The severity and lack of predictability make this a serious issue.
While the cause of ONJ is not known, there is some evidence that inflammation plays a role in the pathogenesis (Wilkinson G S et al 2007). This would explain why patients with inflammatory conditions getting prolonged, high dose steroids have a higher incidence of ONJ.
In theory, co-administration of a steroid for a short duration could decrease inflammation and therefore the incidence of ONJ. However, a study to demonstrate this would not be feasible due to the number of patients it would need to demonstrate an effect. A study comparing the incidence of PDS with Zoledronic acid with a Zoledronic Acid and steroid combination is, however, feasible and such a study has been undertaken.
Eight patients with osteoporosis were treated with Zoledronic Acid alone (3 patients) or with the combination of steroids (oral prednisone, 3, and intravenous prednisolone, 2) with Zoledronic Acid. All three patients who got Zoledronic Acid suffered from PDS. In contrast, none of the patients receiving the combination of steroids and Zoledronic Acid suffered from PDS.
This invention asserts that co-administration of Zoledronic Acid with steroids would thus prevent and treat the side effects of Zoledronic Acid infusion more effectively.